Abstract
We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases= 0.0059, MAFcontrols= 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases= 0.011, MAFcontrols= 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases= 0.0143, MAFcontrols= 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
| Original language | English |
|---|---|
| Pages (from-to) | 1373-1384 |
| Number of pages | 12 |
| Journal | Nature Genetics |
| Volume | 49 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - Sep 2017 |
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Keywords
- Adaptor Proteins, Signal Transducing
- Alzheimer Disease
- Amino Acid Sequence
- Case-Control Studies
- Exome
- Gene Expression Profiling
- Gene Frequency
- Genetic Predisposition to Disease
- Genotype
- Humans
- Immunity, Innate
- Linkage Disequilibrium
- Membrane Glycoproteins
- Microglia
- Odds Ratio
- Phospholipase C gamma
- Polymorphism, Single Nucleotide
- Protein Interaction Maps
- Receptors, Immunologic
- Sequence Homology, Amino Acid
- Journal Article
Cite this
Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. / Sims, Rebecca; van der Lee, Sven J; Naj, Adam C; Bellenguez, Céline; Badarinarayan, Nandini; Jakobsdottir, Johanna; Kunkle, Brian W; Boland, Anne; Raybould, Rachel; Bis, Joshua C; Martin, Eden R; Grenier-Boley, Benjamin; Heilmann-Heimbach, Stefanie; Chouraki, Vincent; Kuzma, Amanda B; Sleegers, Kristel; Vronskaya, Maria; Ruiz, Agustin; Graham, Robert R; Olaso, Robert; Hoffmann, Per; Grove, Megan L; Vardarajan, Badri N; Hiltunen, Mikko; Nöthen, Markus M; White, Charles C; Hamilton-Nelson, Kara L; Epelbaum, Jacques; Maier, Wolfgang; Choi, Seung-Hoan; Beecham, Gary W; Dulary, Cécile; Herms, Stefan; Smith, Albert V; Funk, Cory C; Derbois, Céline; Seripa, Davide; Spalletta, Gianfranco; Bossù, Paola; Fenoglio, Chiara; Serpente, Maria; Arcaro, Marina; Caltagirone, Carlo; Orfei, Maria Donata; Ciaramella, Antonio; Sorbi, Sandro; Bosco, Paolo; Galimberti, Daniela; Scarpini, Elio; Daniele, Antonio; ARUK Consortium.
In: Nature Genetics, Vol. 49, No. 9, 09.2017, p. 1373-1384.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease
AU - Sims, Rebecca
AU - van der Lee, Sven J
AU - Naj, Adam C
AU - Bellenguez, Céline
AU - Badarinarayan, Nandini
AU - Jakobsdottir, Johanna
AU - Kunkle, Brian W
AU - Boland, Anne
AU - Raybould, Rachel
AU - Bis, Joshua C
AU - Martin, Eden R
AU - Grenier-Boley, Benjamin
AU - Heilmann-Heimbach, Stefanie
AU - Chouraki, Vincent
AU - Kuzma, Amanda B
AU - Sleegers, Kristel
AU - Vronskaya, Maria
AU - Ruiz, Agustin
AU - Graham, Robert R
AU - Olaso, Robert
AU - Hoffmann, Per
AU - Grove, Megan L
AU - Vardarajan, Badri N
AU - Hiltunen, Mikko
AU - Nöthen, Markus M
AU - White, Charles C
AU - Hamilton-Nelson, Kara L
AU - Epelbaum, Jacques
AU - Maier, Wolfgang
AU - Choi, Seung-Hoan
AU - Beecham, Gary W
AU - Dulary, Cécile
AU - Herms, Stefan
AU - Smith, Albert V
AU - Funk, Cory C
AU - Derbois, Céline
AU - Seripa, Davide
AU - Spalletta, Gianfranco
AU - Bossù, Paola
AU - Fenoglio, Chiara
AU - Serpente, Maria
AU - Arcaro, Marina
AU - Caltagirone, Carlo
AU - Orfei, Maria Donata
AU - Ciaramella, Antonio
AU - Sorbi, Sandro
AU - Bosco, Paolo
AU - Galimberti, Daniela
AU - Scarpini, Elio
AU - Daniele, Antonio
AU - ARUK Consortium
PY - 2017/9
Y1 - 2017/9
N2 - We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases= 0.0059, MAFcontrols= 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases= 0.011, MAFcontrols= 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases= 0.0143, MAFcontrols= 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
AB - We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases= 0.0059, MAFcontrols= 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases= 0.011, MAFcontrols= 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases= 0.0143, MAFcontrols= 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
KW - Adaptor Proteins, Signal Transducing
KW - Alzheimer Disease
KW - Amino Acid Sequence
KW - Case-Control Studies
KW - Exome
KW - Gene Expression Profiling
KW - Gene Frequency
KW - Genetic Predisposition to Disease
KW - Genotype
KW - Humans
KW - Immunity, Innate
KW - Linkage Disequilibrium
KW - Membrane Glycoproteins
KW - Microglia
KW - Odds Ratio
KW - Phospholipase C gamma
KW - Polymorphism, Single Nucleotide
KW - Protein Interaction Maps
KW - Receptors, Immunologic
KW - Sequence Homology, Amino Acid
KW - Journal Article
U2 - 10.1038/ng.3916
DO - 10.1038/ng.3916
M3 - Article
C2 - 28714976
VL - 49
SP - 1373
EP - 1384
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 9
ER -